The long-term goal of this project is to understand genetic susceptibility to cardiovascular disease (CVD) in kindreds with familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG), the two most common familial forms of hyperlipidemia, using data from 105 kindreds originally studied in Seattle in the early 1970s. During the first four years of the project, 3 specific aims are currently being addressed, as follow: 1) to determine if 20-year total mortality and CVD mortality are increased in these familial disorders; 2) based upon new blood samples, to examine the inheritance of lipoprotein risk factors, especially small, dense low-density lipoproteins (LDL subclass phenotype B); and 3) to establish a repository of white blood cells and plasma for genetic studies. The project proposed here, a competitive renewal, will extend these studies by building on updated pedigree information, laboratory and questionnaire data, and more than 600 blood samples, with three new specific aims, as follow: 1) in order to elucidate the genetic basis of small, dense low-density lipoprotein, map the chromosomal location(s) of gene(s) influencing this phenotype using a whole genome screen; 2) to reveal common genetic influences (pleiotropic effects) on combinations of inter-related lipoprotein risk factors, to refine the phenotypes used in genetic mapping, to characterize genetic-environmental interactions, and to perform multivariate complex segregation analysis (using the size of major LDL subclass, triglyceride, high-density lipoprotein cholesterol, and plasma levels of apolipoproteins A1 and B); and 3) based on 20-year follow-up mortality data in the older, proband generation already obtained, and on additional cardiovascular morbidity data, evaluate familial CVD risk by determining the association between CVD in the proband generation and lipoprotein phenotypes, including lipoprotein(a), in the younger, offspring generation in specific forms of familial hyperlipidemia. The investigators state that the studies proposed in this renewal application represent important and feasible ways to characterize genetic susceptibility to CVD in high risk families. They further state that the next steps in this research will be to perform family-based association studies to identify susceptibility alleles, to characterize the biological functions of newly identified susceptibility genes and to use the new findings on genetic-environmental interactions involving modifiable risk factors to develop targeted intervention strategies for risk reduction in genetically susceptible individuals.